The present invention relates to 5-(chlorophenyl)-6H-1,3,4-thiadiazine-2-amines, having anticonvulsant and anxiolytic activity.
As a general class, 5-(optionally substituted phenyl)-6H-1,3,-4-thiadiazine-2-amines are known as chemical intermediates. See, for example, Japanese Patents 74-110,696, 74-110,697 and 74-100,080. Many individual species related to the compounds of this invention are also known as chemical intermediates. See, for example:
1. Japanese Patent 75 37651;
2. McLean et al, J. Chem. Soc. 1937, 556-9;
3. Avramovici, Analele stiint. univ. "Al. I. Cuza" lasi, Sect. 1 (Mat. Fiz., chim.). (N.S.) 1, 315-319 (1955). CA51:10541;
4. Beyer et al, Justus Liebigs Ann. Chem. 741, 45-54 (1970);
5. Japanese Pat. No. 74-110,696;
6. Japanese Pat. No. 74-110,697;
7. Bose, Quart. J. Indian Chem. Soc. 1, 51-62 (1924).
8. Beyer et al, Chem. Ber. 89, 107-14 (1956);
9. Japanese Pat. No. 74-88,889;
10. Japanese Pat. No. 74-100,080;
11. Bose, Quart. J. Ind. Chem. Soc. 2, 95-114 (1925).
12. Bose et al, J. Indian Chem. Soc. 7, 733-9 (1930);
13. Bulka et al, Z. Chem. 15(12), 482 (1965);
14. Schmidt et al, Tetrahedron Lett. 1975 (1), 33-6;
15. Beyer, Quart. Rep. Sulfur Chem. 5(3), 177-89 (1970);
16. Saraswathi et al, Indian J. Chem. 10(12), 1151-4 (1972);
17. Hampel, Z. Cham. 9(2), 61-2 (1969);
18. Pfeiffer et al, Z. Chem. 17(6), 218-20 (1977);
19. Pfeiffer et al, Synthesis 1977(7), 485-6; and
20. Pfeiffer et al, Synthesis 1977(3), 196-8. Certain species are further known as flame retardants (Japanese Pat. No. 74-5439).
Moreover, some 2-amino-1,3,4-thiadiazines are generally known to have antiviral, antiinflammatory and analgesic activity (Japanese Pat. No. 74-88889). Additionally, many individual species related in structure to the compounds of this invention are disclosed in this same reference. Some species have been found ineffective as vitamin B substitutes (Robbins et al, Proc. Natl. Acad. Sci. U.S. 24, 141-5 (1938) and antitubercular agents (Ban., J. Pharm. Soc. Japan 73, 533-7 (1953) and Bilinski et al, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 13(6), 393-6 (1965)).
Other compounds having significantly different structures are also known to possess pharmacological activity.
4-methyl-4H-5,6-dihydro-1,3,4-thiadiazin-2-amines are known to be CNS active (U.S. Pat. No. 3,428,631 and Trepanier et al, J. Med. Chem. 10(6), 1085-7 (1967)). Additionally, 3-substituted-1,2-dihydro-1,3,4-thiadiazin-2-imines are known as slow cure accelerators for rubber (U.S. Pat. No. 2,871,237).
The 5-membered ring-containing 2-amino-1,3,4-thiadiazoles are known to possess CNS depressant activity (Maffii et al, Il Farmaco (Pavia) Ed. Sci. 13, 187-217 (1958); Great Britain Pat. No. 815,188; W. German Pat. No. 2,212,245 (or Great Britain Pat. No. 1,380,136); U.S. Pat. No. 3,965,110; U.S. Pat. No. 4,054,665; U.S. Pat. No. 3,919,428; and U.S. Pat. No. 3,992,396) and antihypertensive activity (U.S. Pat. No. 3,746,716).
These 5-membered ring-containing 1,3,4-thiadiazole-2-amines are a class of compounds treated by the prior art as distinct from the 6-membered ring-containing 1,3,4-thiadiazin-2-amines. However, the preparation of both types of compounds are reported together by Rao, Khim. Geterotsikl. Soedin. 1977(3), 291-310, as does Klosa, Arch. Pharm. 287, 12-14 (1954). In the latter reference, the compounds are reported as potential, but untested, tuberculostatics. Compounds of both types are also disclosed in Japanese Pat. No. 74 5439 as fire retardants.